Acta Medica OkayamaVolume 14, Issue 2 1960 Article 2

JUNE 1960

Studies on the iron metabolism oferythroblasts in various blood diseases

Ikuro Kimura∗ Tsuyoshi Miyake†

Ri-ichi Kodani‡

∗Okayama University,†Okayama University,‡Okayama University,

Copyright c©1999 OKAYAMA UNIVERSITY MEDICAL SCHOOL. All rights reserved.

Studies on the iron metabolism oferythroblasts in various blood diseases∗

Ikuro Kimura, Tsuyoshi Miyake, and Ri-ichi Kodani

Abstract

The serum iron contents and the number of sideroblasts from various patients and the radioac-tivity of erythroblasts from the same patients incubated with Fe55 have been observed. The resultshave proved that in the case with accelerated erythropoietic function like polycythemia vera and inthe iron deficient state like idiopathic hypochromic anemia, the serum iron level and the numberof sideroblast are lower than those in normal persons and higher in radioactivity in erythroblasts,whereas in the case with low erythropoietic function like hypoplastic anemia the former valuesare higher and lower in radioactivity of erythroblasts. There is an inverse correlation betweenthe average number of stainable iron granules and the average rate of radioactive iron appearancein erythroblasts, and the observation on these factors will give an important clue for judging theutilization process of iron in each disease. The limitation of the iron uptake correlating with thehemoglobin synthesis have been discussed.

∗Copyright c©OKAYAMA UNIVERSITY MEDICAL SCHOOL

Acta Med. Okayama 14, 105-117 (1960).

STUDIES ON THE IRON METABOLISM OF ERYTHROBLASTS

IN VARIOUS BLOOD DISEASES

Ikuro KIMURA, Tsuyoshi MIYAKE

and Ri-ichi KODANI

Department of Internal Medicine, Okayama University Medical SchoolOkayama, Japan (Director: Prof. K. HIRAKI)

Received for publication, Oct. 31, 1959

Owing to the application of radioisotopes with the advanced techniqueof autoradiography, the metabolic pathway ofiron, the absorption, storage,excretion and the incorporation into heme, have been greatly revealed indetail (1, 2, 3, 4). In the meanwhile, the studies on sideroblasts, theerythroblasts containing the iron granules which give positive reaction toblue Prussian, have brought forth a new cytological problem on the non­hemin iron in the cell.

Our previous investigations on these sideroblasts suggested that theiron detectable in erythroblasts by Prussian blue reaction indicated theiron being taken up from serum into the cytoplasm and destined to be in­corporated into heme, and we noted that in the course of the hemoglobinmetabolism iron passed through essentially three steps, the uptake by thecell, retention in the cytoplasm and the incorporation into protoporphyrine(6), though there are some limitations on the transfer of iron from seruminto erythroblasts. The data from which the just mentioned conclusionhas been deduced are those obtained from the chemical and morphologicalobservations by using non-radioactive iron as the iron source.

In the present paper the authors present the evidences to prove thatthe observation on autoradiographic examination and sideroblasts will givean important clue for judging the mechanism of the disturbances in ironmetabolism of erythroblasts in various diseases.

MATERIALS AND METHODS

Experimental materials used are the sera and bone marrow of 21 casesincluding three normal persons, three idiopathic hypochromic anemia,three Banti's disease, three gastric cancer, one hepatic cancer, one Ho­dgkin's disease, one multiple myeloma and one polycythemia vera, threeleukemia and two hypoplastic anemia.

105

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106 K. KIMURA, T. MIYAKE and R. KODANI

As for the experimental method, the serum iron contents are measuredby Barkan's method (7), and the detection of sideroblasts are conductedwith smears of the bone marrow aspirated from patients. At the sametime, 4 fl.c (lr) Fe55 is added to 1 ml of the serum from the patient, andthe mixture is left standing for one hour. Then 0.3 ml aspirated bonemarrow of the same patient is added to the mixture. After keeping thelatter mixture in a roller tube at the constant temperature of 37 u C for 24hours, smears are prepared and autoradiographs of erythroblasts are taken.Since this experiment takes a relatively long time, the radioisotope Fe55,

possessing a longer half-life, has been used. Finally, the sideroblast ap­pearance of the patient and the results of the autoradiography from thesame patient are compared in the manner as to be described later.

For the detection of sideroblasts we have used a modified method ofKAPLAN (5), and observing 100 erythroblasts the percentage of sideroblastshas been calculated, classifying into three types as shown in Fig. 1, ac­cording to the number of iron granules found in the cytoplasm; then plac­ing the percentage of each type at ordinate and type of sideroblast at ab·scissa, a sideroblastogram has been made (6). Also the average number ofiron granules in individual erythroblasts has been calculated.

Fig. 1. Diagrammatical Drawing of Sideroblasts and their Classification.

GGG0la lb~

I

n ][ (type)

Type I possessing 1-2 iron granulesla possessing 1 granulelb possessing 2 granules

Type n possessing 3-5 granulesType ][ possessing over 6 granules

The stripping emulsion method is used for antoradiography. Namely,the bone marrow smears are dried and fixed with methanol. These arefirst treated with gelatin and then these smears are covered with strippingfilm in a dark room. This covering is conducted in 1 % glycerine distilledwater solution added with KBr at the concentration of 50 mg/I. After de­siccating the smears, these are placed in a box containing silicagel, sealedtightly and shielded from light, and the exposure is conducted for 15 daysin a refrigerator. They are developed on Fuji FD-lll for three minutes,and then are immersed in the fixing solution of 1 mol. sodium thiosulfate.

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Iron Metabolism of Erythroblasts 107

The films are washed in running water for 20 minutes, and after dryingthey are stained with Giemsa, and the appearance of darkened silver granu­les on erythroblasts has been observed with microscope.

The erythroblasts are classified into five types, as demonstrated inFig. 2, according to the rate of appearance of darkened silver granuleswith radioactivity. The average rate of radioactive iron appearance inindividual cells is calculated from the distribution density curve drawn onthe 200 cells observed.

Fig. 2. Diagrammatical Drawing of Erythroblasts and the Classificationaccording to the Rate of Radioactive Iron Appearance

in Autoradiography.

Stage of appearance

@ @ ± Low

(j) @ + Intermediate

@ @ -1+-

High

~ @ -Ht0••"

• @. IHI Extremely high:=....:.~~i

RESULTS

Sideroblasts observed by Prussian blue reaction:The investigations of sideroblasts conducted on the bone marrow

smear from the patients in iron deficient state (idiopathic hypochromicanemia, Banti's disease and malignant tumor), and polycythemia vera, inwhich the accelerated erythropoietic function is supposed, proved the lowrate of sideroblast appearance as shown in Figs. 3·A, 4-A, and the side·roblastogram showed a tendency to left shift as can be seen in Figs. 3-B,4-B.

On the contrary, in the cases of hypoplastic anemia and leukemia, inwhich the decreased erythropoietic function is supposed, the sideroblastappearance is high, as indicated in Fig. 6-A and also a tendency to rightshift in sideroblastogram can be recognized as seen in Fig. 6-B.

In the normal persons the values are found to be intermediate betweenthe two groups, the activated and suppressed ones in hematopoiesis (Fig. 5).

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108 K. KIMURA, T. MIYAKE and R. KODANI

Fig. 3. A. Myelogram concerning Sideroblasts and Radioactivity in OneCase of Idiopathic Hypochromic Anemia (Iron Deficient State)

!Z1 I type

~ I1 type

.ra III type

% %100 50 o

ITI±

~+

~ -H-

III ·Ht

•lit!nr;

.....~~ .~ .~

u~ ·Z um '8 Os

~ m Q)

:0 ~ bO :.c ~ :.c ~

-~ E 0 l: 00 .0 ..... Q, ~

Q,0 ...

~ om 0 0 .c 0 .cQ) ... m ... u m ... u

'"e .c >. Cl! -S 0 et: .c 0

in 7"~ etl ~ etl u~:-"l('j >. >.

- Q) "0 ... "0 ...~~ Po.. 0 Po.. 0...

'"'"--- - -"--- ..-----------" '~-~...-------'

Macroblasts Not=moblasts

Fig, 3. B. Sideroblastogram and Fe55 Uptake in each maturing Stage ofErythroblasts

J/o 0/0

100 SO

-----Basophilic.----------Polychromatic- -- - - - -Orthochromic---Total erythroblasts

o I 1I ill (type) ± -i- -i+ -lH- TtH (stage)

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Iron Metabolism of Erythroblasts

Fig. 4. A. Myelogram concerning Sideroblasts and Radioactivity in One Ca!'eof Polycythemia Vera (Accelerated Erythropoietic Function)

109

% %

0 J Type 100 - - SO::.:

-~ JJ Type

11 III Type

r-- ;;~.

:

~:~:: ~..-

~:.......

Cl l777J

~.:.;:; -.,

.... VJ~ ] ~u

~ ~u

VJ .... Q) '5 '5C'J VJbl) :a C'J :a C'J:0 !:!C'J S 0 S 00 .&J .... 0. ... 0. ...

o VJ 0 0 .c 0 0 .c... ... VJ ... U VJ ... UQ).c>' C'J .c 0 C'J .c 0"C .... - ~ u

~ ~ u~i.ii ;.. ... >. >.

... C'J '0 ... '0 ...Q.j~ 0 00 P. P....~

--~-- ....---./ ~--- . ..------"

Macroblasts Normoblasts

0

En~ +

R *III *• tm

Fig. 4. B. Sideroblastogram and FeM Uptake in Each Maturing Stage ofErythroblasts

---Basophilic'.'._-".'- Polychromatic

Orthochromic---Total erythroblasts

o I n

0/0 %

100 50

lIT (type) ± * mJ (stage)

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110 K. KIMURA, T. MIYAKE and R. KODANI

Fig. 5. A. Myelogram concerning Sideroblasts and Radioactivity in One Caseof Normal Person

0/0 %

m3 I Type 100 50

~ II Type

• III Type

~________ii--__~ ""__ _

...rIl10

:0o...v"0iIi

rIl ......"'vrIl bO~ce.0'"o rIl... >."c_.......>'10... Vv~o...

p...

~10eo...

"C\,I>.'0p...

~~

Macroblasts Normoblasts

Fig. 5. B. Sideroblastogram and Fe55 Uptake in Each Maturing Stage ofErythroblasts

% %100 . 50

---Basophilic-----------Polychromatic.- - - - - -Orthochromic

Total erythroblasts

'" ~~ ..... ,"­" ,~

;<,

" "-, ," ,, ," ,, ,. '­----..---.----~--J---...---_-==::;::==-.::::--- -_-==-- _

o I n lIT (type) ± + * +H- tttt (stage)

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Iron Metabolism of Erythroblasts 111

Fig. 6. A. Myelogram concerning Sideroblasts and Radioactivity in One Caseof Hypoplastic Anemia (Low State of Erythropoietic Function)

% %

0-

:::.:;

~+

~*III -Ht

• ttH

~.<.:'.".-::".-:.

".":.

\)

~Q) ~ ,!:! t.>~ .!:! .!:!... '5 ... e~tlIJ :a co :a co

-co c. e 0 c. e 0.0 ... '"' '"'OUl 0 0 .c 0 0 .c'"' Ul '"' U Ul '"' g.c>. (C .c 0 co .c... - P=i u .c P=i u .c>.'"' >. ... >. ...'"' co '0 '"' '0 '"'Q) Q) 0 0c.~ p., p.,0...

p., ~ ~Macroblasts Normoblasts

100- 50C' I Typ~

lTI II Type

m III Type

Fig. 6. B. Sideroblastogram and Fe55 Uptake in Each Maturing Stage ofErythroblasts

% %lOO 50

---Basophilic••...•.•.•. Polychromatic-- - - - --Orthochromic---Total erythroblasts

o I n ]I (type)

\

\'" ./\ .}.

: \... \.,' \\

\\.....

±

... .....

+ * -Ht tttJ (stage)

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112 K. KIMIJRA, T. MIYAKE Ilnn R. KOfJANI

Concerning the average number of stainable iron granules of erythro­blasts, the number is high in hypoplastic anemia and in leukemia, followedby normal persons, and decreases in the order of Banti's disease, cancers,polycythemia vera, idiopathic hypochromic anemia.

-Quantitative analysis of serum iron conducted simultaneously on thesepatients showed some correlation of the serum iron contents to the appea­rance of siderohlasts, i. e. low values in the cases of accelerated erythro­poietic function as one patients in iron deficient state, and high in the caseof low erythropoietic function.

Radioactivity of erythroblasts :The autoradiographic observations revealed that the most marked

radioactivity are found in the polychromatic erythroblasts, followed byorthochromatic erythroblasts, though some of basophilic ones show a highradioactivity. Most of orthochromic erythroblasts showed radioactivitybut low in grade and ones showing high radioactivity can hardly be re­cognized.

In normal persons, a representative case of which is shown in Fig. 5,the erythroblasts having radioactive iron can be recognized, but theyoccupy about 70 per cent of total erythroblasts and the majority of themshow a moderate to low activity and those having a high radioactivity area few in number.

Viewing the radioactivity of erythroblasts in each disease, in thosediseases that show iron deficiency and hypochromic anemia, such as idio­pathic hypochromic anemia, Banti's disease, malignant tumors, generallyalmost all erythroblasts possess radioactivity as in the representative caseof idiopathic hypochromic anemia shown in Fig. 3, and their radioactivitiesare high. For example, in idiopathic hypochromic anemia the radioactiveiron appears in 94.7-97.1 per cent of erythroblasts, and about 70-80 per centof them show a moderate to high radioactivity. In Banti's disease theradioactivity can be recognized in 85.9-93.9 per cent of erythroblasts, andthe majority of them present a moderate radioactivity, and some of themshow a low activity and others a high radioactivity, In Hodgkin's disease,radioactive iron appears in 94 per cent of erythroblasts. Most of them,about 75 per cent, show a moderate to a high radioactivity presenting fairlysimilar values to those of idiopathic hypochromic anemia. In cancers(gastric and hepatic cancers) the radioactive iron appears in 70-94.3 per centof erythroblasts, and most of them show either a moderate or high radioac­tivity in two cases, while the other two cases show a moderate or lowactivity showing a fairly wide range in distribution, though even in theformer the degree of appearance of radioactive iron is lower than what can

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Iron Metabolism of Erythroblasts 113

be observed in idiopathic hypochromic anemia. In these four cases men­tioned above, the appearance of radioactive iron is higher than in the casesof normal persons. In multiple myeloma radioactive iron appears in 90.1 percent of erythroblasts, and many of them, about two thirds in number, showmoderate or high degree of radioactivity and a few of them presented anextremely high radioactivity.

In the case of polycythemia vera which will mean an accelerated ery­thropoiesis, erythroblasts without radioactivity occupy as high as 32.4 percent, and most of radioactive erythroblasts show a high radioactivity(Fig. 4)

In the cases of. hypoplastic anemia and leukemia which will be in thestate of low erythropoietic function radioactive iron appears only in about50-70 per cent of erythroblasts, and moreover, the majority of them, asshown by the representative case of hypoplastic anemia in Fig. 6, showonly an extremely low degree of radioactivity. In the cases of hypopla­stic anemia one--case--shows a -low or intermediate degree of radioactivityin 55.6 per cent of erythroblasts but no erythroblasts with high radioac­tivity can be recognized. In another case, however, 73.2 per cent oferythroblasts showed the radioactivity, and of them about 80 per centpossess low or moderate activity, and about 20 per cent possess the highactivity, showing the conditions rather similar to those of normal persons.In the case of leukemia, radioactivity can be recognized in 57.6 per centof the erythroblasts in one case and these, like in hypoplastic anemia,show only a low to moderate redioactivity. While in another case of leu­kemia 99.1 per cent of erythroblasts show radioactivity and about 90 percent of them showed a moderate to high radioactivity.

On comparing the appearance of radioactive iron in erythroblasts, itis the highest in idiopathic hypochromic anemia, followed by polycythemiavera, Banti's disease, malignant tumors, and normal persons, leukemia,hypoplastic anemia, in the descending order mentioned, as shown in Fig.7. However, in some of malignant tumors and leukemia, the appearancerate is found to be in the range equal to or more than that of idiopathichypochromic anemia, and even in the hypoplastic anemia, the exceptionalcase in which the rate of appearance is close to the normal level can alsobe recognized.

As can be understood from the above mentioned data, between theaverage rate of radioactive Iron appearance in erythroblasts and the ave­rage number of stainable iron granules of erythroblasts there can be ob­served an inverse correlation which is clearly shown in Fig. 8, i. e. thereoccurs a decrease in the appearance of radioactive iron when stainable

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114 K. KIMURA, T. MIYAKE and R. KODANI

iron granules in erythroblasts are on the increase, while the radioactiveiron increases when the stainable iron granules are on the decrease.

Fig. 7. Average Number of Stainable Iron Granules and Average Rate ofRadioactive Iron Appearance in Erythroblasts of Various Diseases

Average rate of radioactive ironappearance in erythroblast

idiopathichypochromicanemia

•cancer,

I polycythemiavera .

• .Banti'sdisease-normalperson

leukemia

hypoplasticanemia

3.0 2.0 1.0

Average number of stainable irongranules in erythroblast

3.0 6.0

Fig. 8. Correlation Between the Average Number of Stainable IronGranules and Average Rate of Radioactive Iron Appearance

X '\l

,. = -0.83

x

o

6.0x

3.0

o

o

o

If,Q;

:5c:~...bO

c: 3.00

.l::Cl)

:0c;l

c:-BUl

....0...Cl)

.0E:Ic:Cl)

blIell...Cl)

><

Average rate of radioactive iron appearance

o Hypoplastic anemiaD Leukemiao Normal personX Cancer

• Banti's disease• Polycythemia vera• Idiopathic hypochromic anemiaV Hodgkin's disease

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Iron Metabolism of Erythroblasts

DISCUSSION

115

The autoradiography of erythroblasts in vitro reveals the Fe55 takeninto erythroblasts and it is quite a convenient methnd for tracing the in­troduction of iron into erythroblasts, but not possible in distinguishingnon-hemin iron from heme iron.

In contrast to this, the investigation of the iron granules stainable byPrussian blue reaction in erythroblast, sideroblasts, reveal the non-heminiron in the cell, which is supposed to be on its way to hemoglobinproduction after iron is taken up by erythroblast. (6) Consequently it isreasonable to think that more precise knowledge about the iron metabolismin erythroblasts may be obtained by combining the autoradiography methodwith the potassium ferrocyanide method. Howerver, it has been proventhat there are some difficulties technically to investigate the radioactivityon the cells having the Prussian blue reaction on the same specimen. There­fore, we have investigated the iron uptake by applying the autoradiographicmethod on one specimen and the pathway of the iron taken into cell tothe heme synthesis by the potassium ferrocyanide method on another spe­cimen from the same patient. Comparative studies on these two specimengave a fruitful results revealing the correlation between these as demon­strated in above.

The results have shown that in idiopathic hypochromic anemia, a re­presentative one of iron deficiency cases as already mentioned, both serumiron and sideroblasts are low in their values and a marked iron uptake canbe recognized in erythroblasts, clearly indicating the accelerated ironuptake into the erythroblast and an increa3ed incorporation into heme.Similar results have been also obtained in Banti's disease suggesting thatin Banti's disease there is hardly any disturbance of the erythropoieticfunction in the bone marrow, and solely the detention of iron in the re­ticuloendothelial system mainly in the spleen brings about a poor supplyof iron to the bone marrow, which will be the main factor for causinganemia in this disease. Even in the cases of malignant tumors, the similartendency as in the previous cases can be recognized of serum iron, sidero­blasts, and the radioactivity of erythroblasts, indicating that in the patientbearing malignant tumors the iron deficiency anemia will be induced bythe fixation of iron in some tissues, probably in cancer tissue or in the re­ticul<>;endothelial system.

In polycythemia vera some erythroblasts show a marked uptake ofFe55

, but there are a considerable number of erythroblasts that show noradioactive iron, and this is ina marked contrast to idiopathic hypochro-

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116 K. KIMURA, T. MIYAKE and R. KODANI

mic anemia in which the number of sideroblasts is markedly decreased andalmost all erythroblasts contain Fe55• In the polycythemia vera there ishardly any iron deficient state in the bone marrow as the erythroblastscontain a considerable amount of hemoglobin, and it is assumed that inpolycythemia vera the process of iron uptake into cell and the incorpora-.tion of iron into heme is proceeding without any disturbance keeping anequilibilium at a certain level of the increased hematopoiesis. Actuallythe bone marrow are filled with a number of the relatively matured eryth­roblasts less in the iron holding capacity (6). In hypoplastic anemia bothserum iron and sideroblasts show high values, while, a decrease in theiron uptake of erythroblasts can generally by recognized. This fact subs­tantiates a decrease in the iron utilization owing to the erythropoietic dis­turbance, though some cases showed the normal iron uptake of erythro­blast.

In leukemia, generally the serum iron level and the number of sidero­blasts are high and low in the number of those containing radioactiveiron, showing the reduction in iron uptake and incorporation into heme,though occationally a marked uptake can be recognized. The irregularityof these data suggests that there are various factors responsible for anemiaor the different factors in the different phases in this disease. Namely,there exist the disturbances of the erythropoietic function or the iron de­ficient state due to the iron detention in the reticuloendothelial system insame cases, and either one of these must have been brought to the surface.

Between the rate of appearance of sideroblasts and the iron uptake asmeasured by autoradiography in various diseases there can generally berecognized an inverse correlation as already mentioned, and this indicatesthat the stainable iron in erythroblast can be a criterion for judging theiron uptake capacity of erythroblasts and also, as we have already pointedout, is associated with the inhibition of the iron incorporation into heme.The maximum number of the stainable iron granules seem to be limitedin a certain level. This suggests the limitations of the iron holding capa­city of erythroblasts in the form of non-hemin iron (6). In other words,even if a quantity of iron is supplied from serum, the iron uptake oferythroblasts is limited by the contents of non-hemin iron in the cell. Themaximum capacity may be correlated to the quantity needed for hemo­globin synthesis in erythroblasts in the course of maturation. The mecha­nism of iron uptake seems to be a relatively simple like a diffusion whichcan be controlled by the saturation grade of the non-hemin iron in the cell.Therefore, one can know in what process or in what extent the iron meta­bolism is inhibited in each disease, if he observes the amount of non-hemin

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Iron Metabolism of Erythroblasts

iron and the radioactivity in erythroblasts.

SUMMARY

117

The serum iron contents and the number of sideroblasts from variouspatients and the radioactivity of erythroblasts from the same patients in­cubated with Fe55 have been observed.

The results have proved that in the case with accelerated erythro­poietic function like polycythemia vera and in the iron deficient state likeidiopathic hypochromic anemia, the serum iron level and the number ofsideroblast are lower than those in normal persons and higher in radioac­tivity in erythroblasts, whereas in the case with low erythropoietic func­tion like hypoplastic anemia the former values are higher and lower inradioactivity of erythroblasts.

There is an inverse correlation between the average number of stain­able iron granules and the average rate of radioactive iron appearancein erythroblasts, and the observation on these factors will give an impor­tant clue for judging the utilization process of iron in each disease. Thelimitation of the iron uptake correlating with the hemoglobin synthesishave been discussed

ACKNOWLEDGMENT

We are greatly indebted to Prof. Kiyoshi 'Hiraki for his invaluable advices andpainstaking proof reading.

REFERENCES

1. AUSTONI, M. E: Autoradiographic studies on iron 59 turnover by erythroid cells inrat bone marrow, Proc. Soc. Exper. BioI. Med., 85, 48, 1954

2. LAJTHA, L. G. and SUIT, H. D.: Uptake of radioactive iron (Fe 59) by nucleated redcells in vitro, Brit. ]. Hematol., I, 55, 1955

3. KIMURA, K. and FUKUI, Y.: Autoradiography of blood cells, Acta HaematoI. ]ap.,19, 358, 1951

4. NAKAO, K. et al: Iron utilization in heme synthesis and erythroblastic nucleus,Acta HaematoI. ]ap., 20, 1, 1959

5. KAPLAN, E. et al. : Sideroblasts, a study of stainable nonhemoglobin iron in marrownormoblasts, Blood, 9, 203, 1954

6. KIMURA I. et al.: Examination of sideroblasts as a means for determining theerythropoietic function of bone marrow, Acta Haematol. ]ap., 21, 727, 1948

7. BARKAN, G. and WALKER, B. S.: Determination of serum iron and pseudo-hemoglobiniron with o·phenanthroline, ]. BioI. Chem., 135, 37, 1940

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